Immunosuppression is routinely used to reduce the risk of rejection in tissue/organ transplantation as well as a therapy for autoimmune and inflammatory disorders, Cyclosporine A (CsA) is currently the most widely used immunosuppressive agent. Tacrolimus (TAC) (also known as FK506) and sirolumus (also known as rapamycin) are two other commonly used immunosuppressants. For review of various immunosuppressive therapies, see, e.g., Schuurman et al. (2001) Modern Immunosuppressives (Milestones in Drug Therapy), Birkhauser, Boston; and Sayegh et al. (2001) Current and Future Immunosuppressive Therapies Following Transplantation, Kluwer Academic Publishers.
Although improved therapeutic strategies have been developed, the adverse side effects associated with immunosuppressive agents remain a significant challenge. Nephrotoxicity is a serious complication of many immunosuppressive therapies, particularly, those that utilize calcineurin inhibitors.
Acute cyclosporine (CsA) toxicity causes nephritis characterized by a decrease in glomerular filtration rate (GFR) and renal blood flow, hypomagnesemia, and tubular injury. Likewise, chronic CsA toxicity results in a progressive state of renal dysfunction characterized by interstitial fibrosis, tubular atrophy, and vascular changes such as arterial ischemia. These changes ultimately lead to end-stage renal disease and renal failure. Nephrotoxicity was, for example, observed in graft recipients treated with tacrolimus (see, e.g., English et al. (2002) Am. J. Transplant., 2:769-273) and sirolumus (see, e.g., Fervenza et al. (2004) Nephrol. Dial. Transplant., 19(5):1288-1292).
Recent studies have implicated Transforming Growth Factor-β (TGF-β) as a mediator of both immunosuppressive activity and/or nephrotoxicity of certain immunosuppressants, including CsA, tacrolimus, and rapamycin (Khanna et al. (2000) Transplantation, 70(4):90-694). Blocking TGF-β in non-transplant models of CsA nephrotoxicity by administration of an anti-TGF-β antibody was shown to substantially reduce overall tissue fibrosis (Khanna et al. (1999) Transplantation, 67:882-889; Islam (2001) 59:498-506; Ling et al. (2003) J. Am. Soc. Nephrol., 14:377-388), however, it also inhibits the immunosuppressive effects of the agents.
A number of experimental strategies have been examined with the goal of reducing nephrotoxicity while retaining immunosuppression in this class of drugs. Agents that may moderate nephrotoxicity by a TGF-β-related but indirect mechanism include: mycophenolate mofetil (MMF) (Shihab et al. (2003) Am. J. Transplant., 3:1550-1559), spironolactone (Feria et al. (2003) Kidney Int., 63:43-52), losartan (Yang et al. (2003) Transplantation, 75:309-315), vitamin E (Jenkins et al. (2001) Transplantation, 71:331-334), pirfenidone (Shihab (2002) Am. J. Transplantation, 2:111-119), and angiotensin receptor blockade (Boffa et al. (2003) J. Am. Soc. Nephrol., 14:1132-1144). However, none are completely satisfactory.
Therefore, there exists a need for treatment modalities that would allow reduced nephrotoxicity of CsA or other immunosuppressive agents, while maintaining their immunosuppressive activity.